Advances in adult acute lymphoblastic leukemia therapy

Aldoss, Ibrahim; Stein, Anthony S.

doi:10.1080/10428194.2017.1354372

Cited by 48 publications

(34 citation statements)

References 140 publications

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“…A number of targeted immunotherapies have been developed to meet this urgent medical need for novel treatments for adults with R/R ALL, including bispecific T‐cell engager (BiTE) molecules, antibody‐drug conjugates and chimeric antigen receptor T cells (CART) . Blinatumomab is a BiTE immuno‐oncology therapy with dual specificity for CD19 and CD3 .…”

Section: Introductionmentioning

confidence: 99%

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Kiyoi

Morris

et al. 2020

Cancer Science

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Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/ day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/ CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL. K E Y W O R D S acute lymphoblastic leukemia, blinatumomab, clinical study, Japan, phase 1b, refractory, relapsed | 1315 KIYOI et al.

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Section: Introductionmentioning

confidence: 99%

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Kiyoi

Morris

et al. 2020

Cancer Science

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“…While tremendous progress has been made in the treatment of pediatric ALL, the success rate of current treatments is much more modest in adults ( Aldoss and Stein, 2018 ). Hence, new therapeutic agents are urgently needed for ALL therapy ( Thu Huynh and Bergeron, 2017 ; Dyczynski et al., 2018a ).…”

Section: Discussionmentioning

confidence: 99%

“…The survival rate of leukemia patients can reach 90% in children under 14 years of age, while it can decrease to 40% in adults between 25 and 64 years of age and to almost 15% in adults aged over 65 (Curran and Stock, 2015;Hunger and Mullighan, 2015;Kansagra et al, 2018). The poor prognosis for the elderly is because of the ease of metastasis to different organs and frequent relapse (Aldoss and Stein, 2018). The most difficult problem is in the treatment of hematologic malignancies is that few treatments show the desired therapeutic efficacy or achieve complete responses (Phelan and Advani, 2018).…”

Section: Introductionmentioning

confidence: 99%

Transcriptome Profiling and Cytological Assessments for Identifying Regulatory Pathways Associated With Diorcinol N-Induced Autophagy in A3 Cells

Yuan

et al. 2020

Front. Pharmacol.

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Fungal secondary metabolites serve as a rich resource for exploring lead compounds with medicinal importance. Diorcinol N (DN), a fungal secondary metabolite isolated from an endophytic fungus, Arthrinium arundinis, exhibits robust anticancer activity. However, the anticancer mechanism of DN remains unclear. In this study, we examined the growthinhibitory effect of DN on different human cancer cell lines. We found that DN decreased the viability of A3 T-cell leukemia cells in a time-and concentration-dependent manner. Transcriptome analysis indicated that DN modulated the transcriptome of A3 cells. In total, 9,340 differentially expressed genes were found, among which 4,378 downregulated genes and 4,962 upregulated genes were mainly involved in autophagy, cell cycle, and DNA replication. Furthermore, we demonstrated that DN induced autophagy, cell cycle arrest in the G1/S phase, and downregulated the expression of autophagy-and cell cyclerelated genes in A3 cells. By labeling A3 cells with acridine orange/ethidium bromide, Hoechst 33,258, and monodansylcadaverine and via transmission electron microscopy, we found that DN increased plasma membrane permeability, structural disorganization, vacuolation, and autophagosome formation. Our study provides evidence for the mechanism of anticancer activity of DN in T-cell leukemia (A3) cells and demonstrates the promise of DN as a lead or even candidate molecule for the treatment of acute lymphoblastic leukemia.

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“…Approximately 20% of pediatric patients and the majority of adults with B-lymphoblastic leukemia (B-ALL) suffer relapse, and prognosis after relapse is very poor. 1,2 Identifying those at risk for treatment failure and devising novel approaches to mitigate their relapse risk is imperative to improving outcome.…”

Section: Introductionmentioning

confidence: 99%

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

Rogers

Gupta

Reyes

et al. 2020

Preprint

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word count: 249 Figures: 7 Supplemental data: 1 supplemental methods and materials file Number of references: 45 Rogers et al. 2 Key points • Engineered IKZF1 perturbations result in a stem-cell like expression signature, enhanced engraftment in vivo, and multi-drug resistance • Loss of IKAROS may result in new vulnerabilities due to increased sensitivity to cytarabine and upregulation of JAK/STAT and mAb targets Rogers et al. 3 Abstract IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-lymphoblastic leukemia (B-ALL). Due to the heterogeneity of concomitant lesions it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance and whether their consideration as a prognostic indicator is valuable in improving outcome. We used CRISPR/Cas9 to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions in order to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment dynamics that can be directly linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of commonly employed therapies for B-ALL including dexamethasone, vincristine, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. We also used a CRISPR homology-directed repair (HDR) strategy to knock-in the dominant-negative IK6isoform tagged with GFP into the endogenous locus and observed a similar drug resistance profile with the exception of retained sensitivity to dexamethasone. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, suggesting intensification of nucleoside analog therapy may be specifically effective for IKZF1-deleted B-ALL. Both types of IKZF1 lesions decreased survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.

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Advances in adult acute lymphoblastic leukemia therapy

Cited by 48 publications

References 140 publications

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Transcriptome Profiling and Cytological Assessments for Identifying Regulatory Pathways Associated With Diorcinol N-Induced Autophagy in A3 Cells

Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

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